The present invention generally relates to a series of compounds, to pharmaceutical compositions containing the compounds, and to use of the compounds and compositions as therapeutic agents. More specifically, compounds of the present invention are tricyclic indeno-pyrrole compounds. These compounds are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders, and conditions wherein modulation of the activity of serotonin receptors (5-HT) is desired (e.g. anxiety, depression and obesity).

Full Text

FIELD OF THE INVENTION
The present invention generally relates to a series of compounds, to
pharmaceutical compositions containing the compounds, and to use of the
compounds and compositions as therapeutic agents. More specifically, compounds
of the present invention are tricyclic indeno-pyrrole compounds. These compounds
are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders,
and conditions wherein modulation of the activity of serotonin receptors (5-HT) is
desired (e.g. addiction, anxiety, depression and obesity).
BACKGROUND OF THE INVENTION
Serotonin has been implicated in a number of diseases, disorders, and
conditions that originate in the central nervous system, including diseases, disorders,
and conditions related to, for example, sleeping, eating, perceiving pain, controlling
body temperature, controlling blood pressure, depression, anxiety, addiction and
schizophrenia. Serotonin also plays an important role in peripheral systems, such as
the gastrointestinal system, where it has been found to mediate a variety of
contractile, secretory, and electrophysiologic effects.
Because of the broad distribution of serotonin within the body, there is
a need for drugs that affect serotonergic systems. In particular, agonists, partial
agonists, and antagonists of serotonergic systems are of interest for the treatment of
a wide range of disorders, including anxiety, depression, hypertension, migraine,
obesity, compulsive disorders, schizophrenia, autism, neurodegenerative disorders
(e.g., Alzheimer's disease, Parkinsonism, and Huntington's chorea), and
chemotherapy-induced vomiting.
The major classes of serotonin receptors (5-HT1-7) contain one to
seven separate receptors that have been formally classified. See Glennon, et al.,
Neuroscience and Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al.
Pharmacol. Rev. 1994, 46, 157-203.
For example, the 5-HT2 family of receptors contains 5-HT2a, 5-HT2b, and

5-HT2c subtypes, which have been grouped together on the basis of primary structure,
secondary messenger system, and operational profile. All three 5-HT2 subtypes are G-
protein coupled, activate phqspholipase C as a principal transduction mechanism, and
contain a seven-transmembrane domain structure. There are distinct differences in the
distribution of the three 5-HT2 subtypes in a mammal. The 5-HT2b and 5-HT2a
receptors are widely distributed in the peripheral nervous system, with 5-HT2a also
found in the brain. The 5-HT2c receptor has been found only in the central nervous
system, being highly expressed in many regions of the human brain. See G. Baxter, et
al. Trends in Pharmacol. Sci. 1995, 16, 105-110.
Subtype 5-HT2a has been associated with effects including
vasoconstriction, platelet aggregation, and bronchoconstriction, as well as certain CNS
effects, while subtype 5-HT2c has been associated with diseases that include
depression, anxiety, obsessive compulsive disorder, addiction, panic disorders,
phobias, psychiatric syndromes, and obesity. Very little is known about the
pharmocologic role of the 5-HT2b receptor. See F. Jenck, et al., Exp. Opin. Invest.
Drugs, 1998, 7, 1587-1599; M. Bos, et al., J. Med. Chem., 1997, 40, 2762-2769; J.R.
Martin, et al., The Journal of Pharmacology and Experimental Therapeutics, 1998,
286, 913-924; S.M. Bromidge, et al.,.1. Med. Chem., 1998,41,1598-1612; G.A.
Kennett, Drugs, 1998, 1, 4, 456-470; and A Dekeyne, et al.,
Neurophannacology,1999, 38, 415-423.
U.S. Patent Nos. 4,622,405; 5,049,564 and 5,244,888 and WO 90/06927
disclose various indeno-pyrrole derivatives.
SUMMARY OF THE INVENTION
The present invention is directed to compounds of the formula:

where
R1 is selected from the group consisting of H, halogen, C1-10alkyl, C2-10alkenyl,
C2-10 alkynyl, perhaloalkyl, CN, N(R6)2, SR6, CON(R6)2, NR6COR7, NR6CO2R7,
SO2N(R6)2, NR6SO2R7, aryl, heteroaryl, C1-10alkylaryl, and C1-10alkylhetroaryl; and
when m+n=1, R1 may also be OR6 or OCOR7;
R2, R3 and R4 are independently selected from the group consisting of H, halogen,
C1-10alkyl, C2-10alkenyl, C2-10 alkynyl, perhaloalkyl, CN, OR6, N(R6)2, SR6, OCOR7,
CON(R6)2, NR6COR7, NR6CO2R7, SO2N(R6)2, NR6SO2R7, aryl, heteroaryl, C1-10
alkylaryl, and C1-10alkylhetroaryl or R2 and R3 together with the ring to which they
are attached form a 5 to 7 membered carbocyclic or heterocyclic ring;
R5 is selected from the group consisting of H, C1-10alkyl, C2-10aIkenyl, C2-10 alkynyl,
perhaloalkyl, CN, OR6, N(R6)2, SR6, OCOR7, CON(R6)2, NR6COR7, NR6CO2R7,
NR6SO2R7, aryl, heteroaryl, C1-10alkylaryl, and C1-10 alkylhetroaryl, or R4 and R5
together with the ring to which they are attached form a 6 to 8 membered aryl or
heteroaryl ring;
R5a is H; or R5 and R5a taken together form a cyclopropane ring;
R6 is selected from the group consisting of H, C1-10alkyl, C2-10alkenyl, C2-10alkynyl,
perhaloalkyl, C1-10alkyl-O- C1-10alkyl, aryl, heteroaryl, C1-10alkyl-O-aryl, C1-10alkyl-
O-heteroaryl, C1-10 alkylaryl, and C1-10 alkylhetroaryl; and
R7 is selected from the group consisting of C1-10alkyl, C2-10alkenyl, C2-10 alkynyl,
perhaloalkyl, C1-10alkyl-O-C1-10alkyl, aryl, heteroaryl, C1-10alkyl-O-aryl, C1-10alkyl-O-
heteroaryl, C1-10 alkylaryl, and C1-10 alkylhetroaryl;
provided that if R1, R2, R5 and R5a are H, then R3 and/or R4 must be H and the
pharmaceuticaliy acceptable salts thereof.
Included herein are the various stereoisomers of the compounds of
Formula (I).

Another embodiment of the present invention provides a
pharmaceutical composition comprising a compound of Formula (I), or a
pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
Still another embodiment of the present invention provides a method of
treating a disease, disorder and/or condition in a mammal (e.g., animal or human),
wherein a 5-HT2c receptor is implicated and modulation of a 5-HT2c function is
desired. The method comprises administering a therapeutically effective amount of
a compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the
mammal.
Yet another embodiment of the present invention comprises a method
of modulating 5-HT receptor function with an effective amount of compound of
Formula (I), or a pharmaceutically acceptable salt thereof.
A further embodiment of the present invention provides a method of
treating or preventing diseases, disorders, and/or conditions of the central nervous
system. The method comprises administering a therapeutically effective amount of a
compound of Formula (I), or a pharmaceutically acceptable salt thereof, to the
mammal.
Specific diseases, disorders and/or conditions for which compounds of
the Formula (I) may have activity include cardiovascular disorders, obesity,
depression, schizophrenia, anxiety, obsessive compulsive disorder, addiction, panic
disorders, sleep disorders, migraine, Type II diabetes, epilepsy, phobias and
psychiatric syndromes.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions are used, unless otherwise described:
As used herein, the term "alkyl" includes straight chained and
branched hydrocarbon groups containing the indicated number of carbon atoms,
typically methyl, ethyl, and straight chain and branched propyl and butyl groups. The
term "alkyl" also encompasses cycloalkyl, i.e., a cyclic C3-C8 hydrocarbon group,
such as cyclopropyl, cyclobutyl, cyclopentyl, and cydohexyl. Reference to an
individual group or moiety, such as "propyl," embraces only the straight chain group
or moiety. A branched chain isomer, such as "isopropyl," is specifically referred to.
The term "alkenyl" as used herein, alone or in combination, refers to a

substituted or unsubstituted straight-chain or substituted or unsubstituted branched-
chain alkenyl radical containing from 2 to 10 carbon atoms. Examples of such
radicals include, but are not,limited to, ethenyl, E- and Z-pentenyi, decenyl and the
like.
The term "alkynyl" as used herein, alone or in combination, refers to a
substituted or unsubstituted straight or substituted or unsubstituted branched chain
alkynyl radical containing from 2 to 10 carbon atoms. Examples of such radicals
include, but are not limited to, ethynyl, propynyl, propargyl, butynyl, hexynyl, decynyl
and the like.
The term "alkoxy" as used herein, alone or in combination, refers to an
alkyi ether radical, wherein the term "alky!" is as defined above. Examples of
suitable alkyl ether radicals include, but are not limited to, methoxy, ethoxy, n-
propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term "halo" is defined herein to include fluoro, chloro, bromo, or
iodo. Similarly, the term "halogen" is defined herein to include fluorine, chlorine,
bromine, and iodine.
The term "amino", alone or in combination, includes the group -NH2 or
-NRaRb wherein Ra and Rb are independently hydrogen, alkyl or aryl.
The term "aryl," alone or in combination, is defined herein as a
monocyclic or bicyclic aromatic group (e.g., phenyl or naphthyl) that can be
unsubstituted or substituted, for example, with one or more, and in particular one to
three of the following substituents selected from the group consisting of H, halo, CN,
NO2, CF3, N3, C1-6 alkyl, OH, NRaRb, OC1-6 alkyl, ORa, C(=O)NRaRb, C(=S)NRaRb,
tetrazoyl, triazoyl, amidinyl, guanidinyl, thioguanidinyl, cyanoguanadinyl, and aryl.
Generally, "aryl" denotes a phenyl group, or an ortho-fused bicyclic carbocyclic
group having nine to ten ring atoms in which at least one ring is aromatic (e.g.
naphthyl or tetrahydronaphthyl). The term "aryl" also is abbreviated in the various
chemical structures as "Ar."
The term "carbocyclic" includes any closed ring of carbon atoms,
including alicyclic and aromatic structures.
The term "heteroaryl" is defined herein as a monocyclic, bicyclic, or
tricyclic ring system containing one, two, or three aromatic rings and containing at
least one nitrogen, oxygen, or sulfur atom in an aromatic ring, and which can be
unsubstituted or substituted, for example, with one or more, and in particular one to

Presently preferred compounds include:
5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;
5-Hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;
5-Methoxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;
5-Hydroxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;
6-Chloro-8-methyl-1,2,3,38,8,8a-hexahydroindeno[1,2-c]pyrrole;
5-(4-Flourobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-
c]pyrrole;
5-Benzyloxy-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;
5-(2-FluorobenzyIoxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-
c]pyrrole;
5-(3-Fluorobenzyloxy)-6-chloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-
c]pyrrole;
1,2,3,3a,8,8a-Hexahydroindeno[1,2-c]pyrro!e;
6-Chloro-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;
6,7-Dichloro-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;
4,5-Dimethoxy-6-chloro-8-methyl-1,2.3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole;
4,6-Dichloro-5-Methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole; and
6-(2,6-Difluorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.
Certain compounds of the invention may exist in different isomeric (e.g.
enantiomers and distereoisomers) forms. The invention contemplates all such
isomers both in pure form and in admixture, including racernic mixtures. Enol forms
are also included.
The compounds of the invention can exist in unsolvated as well as
solvated forms, including hydrated forms, e.g., hemi-hydrate. In general, the
solvated forms, with pharmaceutically acceptable solvents such as water, ethanol,
and the like are equivalent to the unsolvated forms for the purposes of the invention.
Certain compounds of the invention also form pharmaceutically
acceptable salts, e.g., acid addition salts. For example, the nitrogen atoms may form
salts with acids. Examples of suitable acids for salt formation are hydrochloric,
sulfuric, phosphoric, acetic, citric, oxalic, malonic, salicylic, malic, furmaric, succinic,
ascorbic, maleic, methanesulfonic and other mineral carboxylic acids well known to
those in the art. The salts are prepared by contacting the free base form with a

sufficient amount of the desired acid to produce a salt in the conventional manner.
The free base forms may be regenerated by treating the salt with a suitable dilute
aqueous base solution such, as dilute aqueous hydroxide potassium carbonate,
ammonia, and sodium bicarbonate. The free base forms differ from their respective
salt forms somewhat in certain physical properties, such as solubility in polar
solvents, but the acid salts are equivalent to their respective free base forms for
purposes of the invention. (See, for example S. M. Berge, et al., "Pharmaceutical
Salts," J. Pharm. Sci., 66: 1-19 (1977) which is incorporated herein by reference.
As used herein, the term "composition" is intended to encompass a
product comprising the specified ingredients in the specified amounts, as well as any
product which results, directly or indirectly, from a combination of the specified
ingredients in the specified amounts.
The compounds of the present invention can be used in the form of
pharmaceutically acceptable salts derived from inorganic or organic acids. The
phrase "pharmaceutically acceptable salt" means those salts which are, within the
scope of sound medical judgment, suitable for use in contact with the tissues of
humans and lower animals without undue toxicity, irritation, allergic response and the
like and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically
acceptable salts are well-known in the art. For example, S. M. Berge et al. describe
pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1
et seq. The salts can be prepared in situ during the final isolation and purification of
the compounds of the invention or separately by reacting a free base function with a
suitable organic acid. Representative acid addition salts include, but are not limited
to acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,
bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate,
hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide,
hydroiodide, 2-hydroxyethansulfonate (isothionate), lactate, maleate,
methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmitoate, pectinate,
persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,
thiocyanate, phosphate, glutamate, bicarbonate,
p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can
be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl,
and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,
dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl and

stearyl chlorides, bromides and iodides; arylalkyi halides like benzyl and phenethyl
bromides and others. Water or oil-soluble or dispersible products are thereby
obtained. Examples of acids which can be employed to form pharmaceutically
acceptable acid addition salts include such inorganic acids as hydrochloric acid,
hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as
oxalic acid, maleic acid, succinic acid and citric acid.
Basic addition salts can be prepared in situ during the final isolation
and purification of compounds of this invention by reacting a carboxylic acid-
containing moiety with a suitable base such as the hydroxide, carbonate or
bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an
organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts
include, but are not limited to, cations based on alkali metals or alkaline earth metals
such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and
the like and nontoxic quaternary ammonia and amine cations including ammonium,
tetramethylammonium, tetraethylammonium, methylammonium, dimethylammonium,
trimethylammonium, triethylammonium, diethylammonium, and ethylammonium
among others. Other representative organic amines useful for the formation of base
addition salts include ethylenediamine, ethanolamihe, diethanolamine, piperidine,
piperazine and the like.
Dosage forms for topical administration of a compound of this invention
include powders, sprays, ointments and inhalants. The active compound is mixed
under sterile conditions with a pharmaceutically acceptable carrier and any needed
preservatives, buffers or propellants which can be required. Opthalmic formulations,
eye ointments, powders and solutions are also contemplated as being within the
scope of this invention.
Actual dosage levels of active ingredients in the pharmaceutical
compositions of this invention can be varied so as to obtain an amount of the active
compound(s) which is effective to achieve the desired therapeutic response for a
particular patient, compositions and mode of administration. The selected dosage
level will depend upon the activity of the particular compound, the route of,
administration, the severity of the condition being treated and the condition and prior
medical history of the patient being treated. However, it is within the skill of the art to
start doses of the compound at levels lower than required to achieve the desired

therapeutic effect and to gradually increase the dosage until the desired effect is
achieved.
When used in the above or other treatments, a therapeutically effective
amount of one of the compounds of the present invention can be employed in pure
form or, where such forms exist, in pharmaceutically acceptable salt, ester or
prodrug form. Alternatively, the compound can be administered as a pharmaceutical
composition containing the compound of interest in combination with one or more
pharmaceutically acceptable excipients. The phrase "therapeutically effective
amount" of the compound of the invention means a sufficient amount of the
compound to treat disorders, at a reasonable benefit/risk ratio applicable to any
medical treatment. It will be understood, however, that the total daily usage of the
compounds and compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgement. The specific
therapeutically effective dose level for any particular patient will depend upon a
variety of factors including the disorder being treated and the severity of the disorder;
activity of the specific compound employed; the specific composition employed; the
age, body weight, general health, sex and diet of the patient; the time of
administration, route of administration, and rate of excretion of the specific
compound employed; the duration of the treatment; drugs used in combination or
coincidental with the specific compound employed; and like factors well known in the
medical arts. For example, it is well within the skill of the art to start doses of the
compound at levels lower than required to achieve the desired therapeutic effect and
to gradually increase the dosage until the desired effect is achieved.
The total daily dose of the compounds of this invention administered to
a human or lower animal may range from about 0.0001 to about 1000 mg/kg/day.
For purposes of oral administration, more preferable doses can be in the range of
from about 0.001 to about 5 mg/kg/day. If desired, the effective daily dose can be
divided into multiple doses for purposes of administration; consequently, single dose
compositions may contain such amounts or submultiples thereof to make up the
daily dose.
The present invention also provides pharmaceutical compositions that
comprise compounds of the present invention formulated together with one or more
non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions

can be specially formulated for oral administration in solid or liquid form, for
parenteral injection or for rectal administration.
The pharmaceutical compositions of this invention can be administered
to humans and other mammals orally, rectaIly, parenterally , intracisternally,
intravaginally, intraperitoneally, topically (as by powders, ointments or drops), bucally
or as an oral or nasal spray. The term "parenterally," as used herein, refers to modes
of administration which include intravenous, intramuscular, intraperitoneal,
intrasternal, subcutaneous and intraarticular injection and infusion.
In another aspect, the present invention provides a pharmaceutical
composition comprising a component of the present invention and a physiologically
tolerable diluent. The present invention includes one or more compounds as
described above formulated into compositions together with one or more non-toxic
physiologically tolerable or acceptable diluents, carriers, adjuvants or vehicles that
are collectively referred to herein as diluents, for parenteral injection, for intranasal
delivery, for oral administration in solid or liquid form, for rectal or topical
administration, among others.
The compositions can also be delivered through a catheter for local
delivery at a target site, via an intracoronary stent (a tubular device composed of a
fine wire mesh), or via a biodegradable polymer. The compounds may also be
complexed to ligands, such as antibodies, for targeted delivery.
Compositions suitable for parenteral injection may comprise
physiologically acceptable, sterile aqueous or nonaqueous solutions, dispersions,
suspensions or emulsions and sterile powders for reconstitution into sterile injectable
solutions or dispersions. Examples of suitable aqueous and nonaqueous carriers,
diluents, solvents or vehicles include water, ethanol, polyols (propyleneglycol,
polyethyleneglycol, glycerol, and the like), vegetable oils (such as olive oil),
injectable organic esters such as ethyl oleate, and suitable mixtures thereof.
These compositions can also contain adjuvants such as preserving,
wetting, emulsifying, and dispensing agents. Prevention of the action of
microorganisms can be ensured by various antibacterial and antifungal agents, for
example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, for example sugars, sodium chloride and the like.
Prolonged absorption of the injectable pharmaceutical form can be brought about by

the use of agents delaying absorption, for example, aluminum monostearate and
gelatin.
Suspensions, ih addition to the active compounds, may contain
suspending agents, as for example, ethoxylated isostearyl alcohols, polyoxyethylene
sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide,
bentonite, agar-agar and tragacanth, or mixtures of these substances, and the like.
In some cases, in order to prolong the effect of the drug, it is desirable
to slow the absorption of the drug from subcutaneous or intramuscular injection. This
can be accomplished by the use of a liquid suspension of crystalline or amorphous
material with poor water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution which, in turn, may depend upon crystal size and
crystalline form. Alternatively, delayed absorption of a parenterally administered drug
form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices
of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending
upon the ratio of drug to polymer and the nature of the particular polymer employed,
the rate of drug release can be controlled. Examples of other biodegradable
polymers include poly(orthoesters) and poly(anhydrides). Depot injectable
formulations are also prepared by entrapping the drug in liposomes or
microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration
through a bacterial-retaining filter or by incorporating sterilizing agents in the form of
sterile solid compositions which can be dissolved or dispersed in sterile water or
other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets,
pills, powders and granules. In such solid dosage forms, the active compound may
be mixed with at least one inert, pharmaceutically acceptable excipient or carrier,
such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as
starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as
carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia;
c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium
carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators
such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol

and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i)
lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene
glycols, sodium lauryl' sulfate and mixtures thereof. In the case of capsules, tablets
and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in
soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as
well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills and
granules can be prepared with coatings and shells such as enteric coatings and
other coatings well-known in the pharmaceutical formulating art. They may optionally
contain opacifying agents and may also be of a composition such that they release
the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract,
optionally, in a delayed manner. Examples of embedding compositions which can be
used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if
appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically
acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the
active compounds, the liquid dosage forms may contain inert diluents commonly
used in the art such as, for example, water or other solvents, solubilizing agents and
emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate,
benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl
formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and
sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan and mixtures thereof.
Besides inert diluents, the oral compositions may also include
adjuvants such as wetting agents, emulsifying and suspending agents, sweetening,
flavoring and perfumingagents.
Compositions for rectal or vaginal administration are preferably
suppositories which can be prepared by mixing the compounds of this invention with
suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol
or a suppository wax which are solid at room temperature but liquid at body
temperature and therefore melt in the rectum or vaginal cavity and release the active
compound.

Compounds of the present invention can also be administered in the
form of liposomes. As is known in the art, liposomes are generally derived from
phospholipids or other lipid substances. Liposomes are formed by mono- or multi-
lamellar hydrated liquid crystals which are dispersed in an aqueous medium. Any
non-toxic, physiologically acceptable and metabolizable lipid capable of forming
liposomes can be used. The present compositions in liposome form can contain, in
addition to a compound of the present invention, stabilizers, preservatives, excipients
and the like. The preferred lipids are natural and synthetic phospholipids and
phosphatidyl cholines (lecithins) used separately or together.
Methods to form liposomes are known in the art. See, for example,
Prescott, Ed., Methods in Cell Biology,Volume XIV, Academic Press, New York, N.Y.
(1976), p. 33 et seq.
The term "pharmaceutically acceptable prodrugs" as used herein
represents those prodrugs of the compounds of the present invention which are,
within the scope of sound medical judgement, suitable for use in contact with the
tissues of humans and lower animals without undue toxicity, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the zwitterionic forms, where possible, of
the compounds of the invention. Prodrugs of the present invention may be rapidly
transformed: in vivo to the parent compound of the above formula, for example, by
hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella,
Pro-drugs as Novel Delivery Systems,V. 14 of the A.C.S. Symposium Series, and in
Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American
Pharmaceutical Association and Percamon Press (1987), hereby incorporated by
reference.
The compounds of the present invention may be prepared by the
procedures set forth in Schemes 1, 2 and 3. The general analytical conditions set
forth after the Schemes were utilized in all examples.

which was used without further purification. MS calculated for C22H23F2NO2+H: 372,
observed: 372.
Step B. 6-(2,6-DifIuorophenyl)-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrroIe.
The title compound was prepared by the method of Example 10, Step F. The crude
product was purified by reverse-phase liquid chromatography to afford the title
compound. MS calculated for C17H15F2N+H: 272, observed: 272.
Example 13
5-Methyl-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrroIe

Step A. N-E:thylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-
hexahydroindeno[1,2-c]pyrrole. (Scheme 1)
BBr3 in CH2Cl2 (1.1 mL, 1.1 mmol, 1 M) was added to a solution of N-
Ethylcarbamate-5-methoxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
(from Example 2, Step A) (100 mg, 0.36 mmol) at 0 °C. The reaction mixture was
stirred overnight from 0 °C to room temperature and quenched with H2O. The
solution was filtered through an Extrelut column, the column was washed with
CH2Cl2, and the filtrate was concentrated. The crude product was obtained without
further purification. MS calculated for C15H19NO3+H: 262, observed: 262.
Step B. N-Ethylcarbamate-5-benzyloxy-8-methyl-1,2,3,3a,8,8a-
hexahydroindeno[1,2-c]pyrrole.

Benzyl bromide (15 µL, 0.12 mmol) and K2CO3 (70 mg, 0.5 mmol) were added to a
solution of N-ethylcarbamate-5-hydroxy-8-methyl-1,2,3,3a,8,8a-hexahydro
indeno[1,2-c]pyrrole (26 mg, 0.1 mmol) in CH3CN (2 mL). The resulting mixture was
stirred overnight at 80 °C. The reaction was cooled to room temperature,
concentrated by rotary evaporation and taken up in H2O (2.5 mL). The product was
extracted with ethyl acetate (3x5 mL). The combined organic extracts were dried
over MgSO4 and concentrated to afford the subtitle compound, which was used
without further purification. MS calculated for C22H25NO3+H: 352, observed: 352.
Step C. 5-Benzyloxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole.
The title compound was prepared by the method of Example 3, Step B utilizing N-
ethylcarbamate-5-benzyloxy-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole
(0.1 mmol). The crude product was purified by reverse-phase liquid chromatography
to afford the title compound. MS calculated for C19H21NO+H: 280, observed: 280.
Example 44
5-(2-Fluorobenzyloxy)-8-methyl-1,2,3,3a,8,8a-hexahydroindeno[1,2-c]pyrrole

Step A. N-tert-Butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-
aza-cyclopenta[a]inden-8-ol. (Scheme 1)
NaBH4 (4 mg, 0.1 mmol) was added to a solution of N-tert-butyl carbamate-4-chloro-
5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from Example
52, Step D) (20 mg, 0.06 mmol) in MeOH (2 mL), and stirred for 1 hour at room
temperature. The reaction was partitioned between H2O and CH2Cl2, and filtered
through an EExtrelut column. The column was washed with CH2Cl2, and the filtrate
was concentrated. The crude product was obtained without further purification as a
mixture of diastereomers. MS calculated for C17H22CINO4+H: 340, observed: 340.
Step B. 4-chloro-5-methoxy-2,3,3a,3a-tetrahydro-1 H-2-aza-cyclopenta[a]inden-
8-ol.
The title compound was prepared by the method of Example 20, Step I utilizing N-
tert-butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-
cyclopenta[a]inden-8-ol (0.10 mmol). The crude product was purified by reverse-
phase liquid chromatography to afford the title compound. MS calculated for
C12H12CINO2+H: 240, observed: 240.
Example 55
5-Methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-ol

Step A. N-tert-Butyl carbarnate-5-methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-
aza-cyclopenta[a]inden-8-ol.
NaBH4 (4 mg, 0.1 mmol) was added to a solution of N-tert-butyl carbamate-5-
methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-8-one (from
Example 52, Step D, regioisomer) (20 mg, 0.06 mmol) in MeOH (2 mL), and stirred
for 1 hour at room temperature. The reaction was partitioned between H2O and
CH2Cl2, and filtered through an Extrelut column. The column was washed with
CH2Cl2, and the filtrate was concentrated. The crude product was obtained without
further purification as a mixture of diastereomers. MS calculated for C17H22CINO4+H:
340, observed: 340.
Step B. 5-Methoxy-6-chloro-2,3,3a,8a-tetrahydro-1H-2-aza-cyclopenta[a]inden-
8-oI.
The title compound was prepared by the method of Example 20, Step I utilizing N-
tert-butyl carbamate-4-chloro-5-methoxy-2,3,3a,8a-tetrahydro-1H-2-aza-
cyclopenta[a]inden-8-ol (0.10 mmol). The crude product was purified by reverse-
phase liquid chromatography to afford the title compound. MS calculated for
C12H12CINO2+H: 240, observed: 240.

Example 56
Separation of Enantiomers for Selected Compounds of the Invention
The following compounds were separated into their respective enantiomers using a
10 mm x 250 mm Chiral Pak AD-RH chiral column.

3. A pharmaceutical composition comprising at least one compound as claimed in claim 1
or 2 and a pharmaceutically acceptable carrier.

The present invention generally relates to a series of compounds, to
pharmaceutical compositions containing the compounds, and to use of the
compounds and compositions as therapeutic agents. More specifically, compounds
of the present invention are tricyclic indeno-pyrrole compounds. These compounds
are serotonin receptor (5-HT) ligands and are useful for treating diseases, disorders,
and conditions wherein modulation of the activity of serotonin receptors (5-HT) is
desired (e.g. anxiety, depression and obesity).